Kaposi's sarcoma- and B cell lymphoma-associated human herpesvirus 8 (HHV-8) specifies particular proteins that are believed to contribute to angioproliferative and malignant pathogenesis. Key among these is the interleukin-6 homologue, vIL-6, which via its signal transducing properties promotes angiogenesis, cell proliferation and cell survival. The expression of vIL-6 is maximal during lytic, productive replication, but we have demonstrated that it is also expressed as a bone fide latent protein in primary effusion lymphoma (PEL) cells, and, coupled with its predominant intracellular localization, acts in an autocrine manner via ER-initiated intracellular signaling to support PEL growth and survival. Other latency functions of vIL-6, mediated from the ER compartment, may be operative. Unpublished data from this laboratory have established that depletion of latently expressed vIL-6 in PEL cells leads to increased RTA expression and to lytic reactivation, suggesting a role of vIL-6 in regulation of latent-lytic switching. During chemically-induced lytic reactivation, we have found that vIL-6 is a negative regulator of virus production in both endothelial and PEL cells. The present application will focus on the molecular basis of vIL-6 retention and signaling within the ER compartment and the mechanisms and roles of vIL-6 function in relation to virus biology, in part by utilizing the unique reagents and knowledge that we have acquired from our previous studies of vIL-6. The three aims will examine: (1) the roles of ER proteins calnexin and VKORC1 in vIL-6 localization and activity;(2) ER-localized signaling and functions of vIL-6;(3) the role of vIL-6 in the regulation of latent-lytic switching and productive replication. These areas of study are novel and, we believe, of considerable value to future development of anti-viral and therapeutic strategies.

Public Health Relevance

Human herpesvirus 8 (HHV-8) is linked etiologically with endothelial and B cell malignancies and encodes a cytokine homologue, referred to as viral interleukin-6 (vIL-6), which is believed to contribute to disease development, but its role in virus biology is unknown. Our own data have revealed that vIL-6 is essential for growth and survival of cells latently infected with HHV-8 and that it regulates the switch to productive replication and efficiency of virus production. The goal of the proposed research is to characterize the major mechanisms by which vIL-6 functions in these processes, research that will have direct relevance to the development of novel anti-viral strategies that could lead to effective prevention and treatment of HHV-8- associated diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA076445-14
Application #
8676436
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
None
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cousins, Emily; Gao, Yang; Sandford, Gordon et al. (2014) Human herpesvirus 8 viral interleukin-6 signaling through gp130 promotes virus replication in primary effusion lymphoma and endothelial cells. J Virol 88:12167-72
Cousins, Emily; Nicholas, John (2014) Molecular biology of human herpesvirus 8: novel functions and virus-host interactions implicated in viral pathogenesis and replication. Recent Results Cancer Res 193:227-68
Chen, Daming; Gao, Yang; Nicholas, John (2014) Human herpesvirus 8 interleukin-6 contributes to primary effusion lymphoma cell viability via suppression of proapoptotic cathepsin D, a cointeraction partner of vitamin K epoxide reductase complex subunit 1 variant 2. J Virol 88:1025-38
Cousins, Emily; Nicholas, John (2013) Role of human herpesvirus 8 interleukin-6-activated gp130 signal transducer in primary effusion lymphoma cell growth and viability. J Virol 87:10816-27
Nicholas, John (2010) Human herpesvirus 8-encoded cytokines. Future Virol 5:197-206
Chen, Daming; Sandford, Gordon; Nicholas, John (2009) Intracellular signaling mechanisms and activities of human herpesvirus 8 interleukin-6. J Virol 83:722-33
Chen, Daming; Choi, Young Bong; Sandford, Gordon et al. (2009) Determinants of secretion and intracellular localization of human herpesvirus 8 interleukin-6. J Virol 83:6874-82
Nicholas, John (2007) Human herpesvirus 8-encoded proteins with potential roles in virus-associated neoplasia. Front Biosci 12:265-81
Boulanger, Martin J; Chow, Dar-chone; Brevnova, Elena et al. (2004) Molecular mechanisms for viral mimicry of a human cytokine: activation of gp130 by HHV-8 interleukin-6. J Mol Biol 335:641-54
Li, H; Wang, H; Nicholas, J (2001) Detection of direct binding of human herpesvirus 8-encoded interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and identification of amino acid residues of vIL-6 important for IL-6R-dependent and -independent signaling. J Virol 75:3325-34

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